The
impact of nanotechnology and its advancements have allowed
us to explore new therapeutic modalities. To this end, we designed
nanoparticles-inlaid porous microparticles (NIPMs) coloaded with small
interfering RNA (siRNA) and glucagon-like peptide-1 (GLP-1) using
the supercritical carbon dioxide (SC–CO2) technology
as an inhalation delivery system for diabetes therapy. siRNA-encapsulating
chitosan (CS) nanoparticles were first synthesized by an ionic gelation
method, which resulted in particles with small sizes (100–150
nm), high encapsulation efficiency (∼94.8%), and sustained
release performance (∼60% in 32 h). These CS nanoparticles
were then loaded with GLP-1-dispersed poly-l-lactide (PLLA)
porous microparticles (PMs) by SC–CO2-assisted precipitation
with the compressed antisolvent (PCA) process. The hypoglycemic efficacy
of NIPMs administered via pulmonary route in mice persisted longer
due to sustained release of siRNA from CS nanoparticles and the synergistic
effects of GLP-1 in PMs, which significantly inhibited the expression
of dipeptidyl peptidase-4 mRNA (DPP-4-mRNA). This ecofriendly technology
provides a convenient way to fabricate nanoparticle-microparticle
composites for codelivery of a gene and a therapeutic peptide, which
will potentially find widespread applications in the field of pharmaceutics.